SMC6 – A link between DNA repair and glucose metabolism?

Smc5-6 is a highly conserved protein complex related to cohesin and condensin involved in the structural maintenance of chromosomes. In yeasts the Smc5-6 complex is essential for proliferation and is involved in DNA repair and homologous recombination. In order to address the function of the Smc5-6 complex more definitively and to determine its functions in mammals Limei Ju, Jonathan Wing and their colleagues from Alan Lehmann’s laboratory at the Genome Damage and Stability Centre at the University of Sussex in Brighton have analysed two Smc6 mutant mouse strains. A complete knockout resulted in early embryonic lethality, demonstrating that this gene is essential in mammals. The second mutant line carries a mutation of the highly conserved serine-994 to alanine in the ATP hydrolysis motif in the SMC6 C-terminal domain (SMC6.S994A). In the absence of obvious defects, the SMC6-S994A mice were subjected to a detailed examination at the German Mouse Clinic. Morphological inspection and X-ray analysis showed normal morphology, but the mutant mice had a slightly reduced body mass and fat mass but unchanged lean mass. During a modified SHIRPA protocol increased tail elevation and decreased pelvic elevation during walking in a viewing arena was observed, indicating a minor abnormality in muscle or lower motor neuron function. Both male and female mice had significantly longer response times in the hot-plate test which could indicate hypoalgesia. A variety of genotype-related differences were found in the clinical chemistry and haematological analyses. There was a slight decrease in plasma levels of HDL-cholesterol after overnight fasting, and mild increases in glucose and calcium concentrations in ad libitum fed mice. These together with decreased body fat could indicate minor effects on glucose metabolism. It is of interest that impaired glucose tolerance, which was indicated in our mice, has also been reported recently in a patient with the genome instability disorder Werner’s Syndrome. This suggests an as yet poorly understood link between defective DNA damage responses and impaired glucose tolerance. Haematological analysis showed mild to moderate increases of white blood cell, platelet counts, and a trend towards a reduced red blood cell count associated with mild macrocytosis suggested possible effects on hematopoietic proliferation and differentiation. Analysis of immunoglobulin isotype levels in blood plasma (IgG1, IgG2b, IgG3, IgA, and IgM) revealed lower levels of IgG2b in the mutant mice.

L. Ju, et al., SMC6 is an essential gene in mice, but a hypomorphic mutant in the ATPase domain has a mild phenotype with a range of subtle abnormalities, DNA Repair (2013), dx.doi.org/10.1016/j.dnarep.2013.02.006